Roifman syndrome

Summary

Roifman syndrome (MONDO:0014722) is a disease caused by RNU4ATAC (GenCC Definitive), with 3 cohort genes and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: RNU4ATAC (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 25
• Phenotypes (HPO): 39
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		17	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

39 HPO clinical features (Orphanet curated; top 39 by frequency):

HPO ID	Term	Frequency
HP:0000044	Hypogonadotropic hypogonadism	Frequent (30-79%)
HP:0000219	Thin upper lip vermilion	Frequent (30-79%)
HP:0000252	Microcephaly	Frequent (30-79%)
HP:0000316	Hypertelorism	Frequent (30-79%)
HP:0000343	Long philtrum	Frequent (30-79%)
HP:0000403	Recurrent otitis media	Frequent (30-79%)
HP:0000430	Underdeveloped nasal alae	Frequent (30-79%)
HP:0000446	Narrow nasal bridge	Frequent (30-79%)
HP:0000556	Retinal dystrophy	Frequent (30-79%)
HP:0000637	Long palpebral fissure	Frequent (30-79%)
HP:0000964	Eczematoid dermatitis	Frequent (30-79%)
HP:0001156	Brachydactyly	Frequent (30-79%)
HP:0001290	Generalized hypotonia	Frequent (30-79%)
HP:0001433	Hepatosplenomegaly	Frequent (30-79%)
HP:0001511	Intrauterine growth retardation	Frequent (30-79%)
HP:0001795	Hyperconvex nail	Frequent (30-79%)
HP:0001831	Short toe	Frequent (30-79%)
HP:0001880	Eosinophilia	Frequent (30-79%)
HP:0002079	Hypoplasia of the corpus callosum	Frequent (30-79%)
HP:0002342	Intellectual disability, moderate	Frequent (30-79%)
HP:0002655	Spondyloepiphyseal dysplasia	Frequent (30-79%)
HP:0002656	Epiphyseal dysplasia	Frequent (30-79%)
HP:0002714	Downturned corners of mouth	Frequent (30-79%)
HP:0002716	Lymphadenopathy	Frequent (30-79%)
HP:0003273	Hip contracture	Frequent (30-79%)
HP:0004209	Clinodactyly of the 5th finger	Frequent (30-79%)
HP:0004313	Decreased circulating antibody level	Frequent (30-79%)
HP:0004322	Short stature	Frequent (30-79%)
HP:0004625	Biconvex vertebral bodies	Frequent (30-79%)
HP:0005041	Irregular capital femoral epiphysis	Frequent (30-79%)
HP:0006532	Recurrent pneumonia	Frequent (30-79%)
HP:0007598	Bilateral single transverse palmar creases	Frequent (30-79%)
HP:0008804	Broad femoral head	Frequent (30-79%)
HP:0008828	Delayed proximal femoral epiphyseal ossification	Frequent (30-79%)
HP:0008897	Postnatal growth retardation	Frequent (30-79%)
HP:0011231	Prominent eyelashes	Frequent (30-79%)
HP:0410170	Hippocampal atrophy	Frequent (30-79%)
HP:0005419	Decreased T cell activation	Excluded (0%)
HP:0012817	Noncompaction cardiomyopathy	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Roifman syndrome
Mondo ID	MONDO:0014722
MeSH	C535866
OMIM	300258, 616651
Orphanet	353298
UMLS	C1846059
MedGen	375801
GARD	0009163
Is cancer (heuristic)	no

Also known as: RFMN · Roifman syndrome · spondyloepiphseal dysplasia, retinal dystrophy and antibody deficiency · spondyloepiphyseal dysplasia, retinal dystrophy, and antibody deficiency · spondyloepiphyseal dysplasia-retinal dystrophy-immunodeficiency syndrome

Data availability: 25 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › immune system disorder › Roifman syndrome

Related subtypes (46): hypersensitivity reaction disease, immune system cancer, immune system organ benign neoplasm, bone marrow disorder, thymus gland disorder, inborn error of immunity, leukocyte disorder, psoriasis, spondyloarthropathy, aggressive insulitis, benign insulitis, inflammatory bowel disease, autoimmune disease, TNF receptor 1-associated periodic fever syndrome, epidermodysplasia verruciformis, Vici syndrome, proteosome-associated autoinflammatory syndrome, hyperimmunoglobulinemia D with periodic fever, transcobalamin II deficiency, pyogenic arthritis-pyoderma gangrenosum-acne syndrome, granulomatosis with polyangiitis, autosomal recessive osteopetrosis 7, graft versus host disease, congenital sideroblastic anemia-B-cell immunodeficiency-periodic fever-developmental delay syndrome, cryopyrin-associated periodic syndrome, anti-HLA hyperimmunization, acquired immunodeficiency, erythroderma desquamativum, autoinflammatory syndrome with pyogenic bacterial infection and amylopectinosis, familial Mediterranean fever, 22q11.2 deletion syndrome, T-cell large granular lymphocyte leukemia, twin to twin transfusion syndrome, immunodeficiency disease, immunoproliferative disorder, cytokine receptor deficiency, immunodeficiency-related disorder, phagocytic cell dysfunction, thrombocytopenic purpura, lymphoid system disorder, immune reconstitution inflammatory syndrome, growth hormone insensitivity with immune dysregulation 1, autosomal recessive, cytokine release syndrome, early-onset autoimmunity-autoinflammation-immunodeficiency syndrome, CADINS disease, autoinflammation, panniculitis, and dermatosis syndrome

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

25 retrieved; paginated sample, class counts are floors:

10 pathogenic/likely pathogenic, 7 conflicting classifications of pathogenicity, 3 pathogenic, 2 uncertain significance, 2 likely pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1525441	NC_000002.12:g.121530996A>G	CLASP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
218082	NM_001395891.1(CLASP1):c.196-570C>T	CLASP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
218083	NM_001395891.1(CLASP1):c.196-567G>A	CLASP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
218085	NR_023343.3(RNU4ATAC):n.48G>A	CLASP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
218087	NR_023343.3(RNU4ATAC):n.118T>C	CLASP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
30178	NM_001395891.1(CLASP1):c.196-605C>T	CLASP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
30179	NR_023343.3(RNU4ATAC):n.55G>A	CLASP1	Pathogenic	criteria provided, multiple submitters, no conflicts
30184	NR_023343.3(RNU4ATAC):n.50G>A	CLASP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
39443	NR_023343.3(RNU4ATAC):n.124G>A	CLASP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
599282	NM_001395891.1(CLASP1):c.196-594G>A	CLASP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
636959	NR_023343.3(RNU4ATAC):n.46G>A	CLASP1	Pathogenic	criteria provided, multiple submitters, no conflicts
4813621	NR_023343.3:n.16G>A	RNU4ATAC	Pathogenic	criteria provided, single submitter
870579	NR_023343.3(RNU4ATAC):n.116A>G	RNU4ATAC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1803779	NM_001395891.1(CLASP1):c.[196-571C>T];[196-670T>G]		Likely pathogenic	criteria provided, single submitter
812960	NC_000002.12:g.121530995A>T	CLASP1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1403727	NM_001395891.1(CLASP1):c.196-571C>T	CLASP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1944546	NM_001395891.1(CLASP1):c.196-562G>C	CLASP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2151940	NC_000002.12:g.121530892C>G	CLASP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
218084	NM_001395891.1(CLASP1):c.196-591C>T	CLASP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
218086	NR_023343.3(RNU4ATAC):n.8C>T	CLASP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
692041	NM_001395891.1(CLASP1):c.196-607G>A	CLASP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
932368	NR_023343.3(RNU4ATAC):n.18G>A	CLASP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1478923	NR_023343.3(RNU4ATAC):n.66G>A	CLASP1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1989614	NC_000002.12:g.121530980G>A	CLASP1-AS1	Uncertain significance	criteria provided, single submitter
1143919	NM_001395891.1(CLASP1):c.196-679dup	CLASP1	Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 3 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
RNU4ATAC	Definitive	Autosomal recessive	Roifman syndrome	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RNU4ATAC	Orphanet:1824	Lowry-Wood syndrome
RNU4ATAC	Orphanet:2636	Microcephalic osteodysplastic primordial dwarfism types I and III
RNU4ATAC	Orphanet:353298	Roifman syndrome

Cohort genes → proteins

3 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RNU4ATAC	HGNC:34016	ENSG00000264229		RNA, U4atac small nuclear	gencc,clinvar
CLASP1	HGNC:17088	ENSG00000074054	Q7Z460	CLIP-associating protein 1	clinvar
CLASP1-AS1	HGNC:55328	ENSG00000265451		CLASP1 antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CLASP1	CLIP-associating protein 1	Microtubule plus-end tracking protein that promotes the stabilization of dynamic microtubules.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RNU4ATAC	Other/Unknown	no
CLASP1	Other/Unknown	no		ARM-like, ARM-type_fold, HEAT_type_2
CLASP1-AS1	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	2
primordial germ cell in gonad	2
sural nerve	1
cortical plate	1
dorsal motor nucleus of vagus nerve	1
colonic epithelium	1
male germ line stem cell (sensu Vertebrata) in testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RNU4ATAC	116	ubiquitous	marker	primordial germ cell in gonad, sural nerve, calcaneal tendon
CLASP1	286	ubiquitous	marker	cortical plate, calcaneal tendon, dorsal motor nucleus of vagus nerve
CLASP1-AS1	129		yes	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, colonic epithelium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CLASP1	1,686
RNU4ATAC	0
CLASP1-AS1	0

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 2

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CLASP1	Q7Z460	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 15. Enrichment computed across 3 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Role of ABL in ROBO-SLIT signaling	1	634.4×	0.024	CLASP1
Loss of Nlp from mitotic centrosomes	1	79.3×	0.026	CLASP1
Loss of proteins required for interphase microtubule organization from the centrosome	1	79.3×	0.026	CLASP1
RNA polymerase II transcribes snRNA genes	1	77.2×	0.026	RNU4ATAC
AURKA Activation by TPX2	1	76.1×	0.026	CLASP1
Recruitment of mitotic centrosome proteins and complexes	1	68.0×	0.026	CLASP1
Regulation of PLK1 Activity at G2/M Transition	1	63.4×	0.026	CLASP1
Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal	1	58.3×	0.026	CLASP1
Recruitment of NuMA to mitotic centrosomes	1	58.3×	0.026	CLASP1
Anchoring of the basal body to the plasma membrane	1	56.5×	0.026	CLASP1
EML4 and NUDC in mitotic spindle formation	1	46.4×	0.029	CLASP1
Resolution of Sister Chromatid Cohesion	1	43.3×	0.029	CLASP1
RHO GTPases Activate Formins	1	38.8×	0.030	CLASP1
Mitotic Prometaphase	1	34.6×	0.031	CLASP1
Separation of Sister Chromatids	1	30.4×	0.033	CLASP1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of microtubule polymerization or depolymerization	1	5617.3×	0.002	CLASP1
establishment of mitotic spindle localization	1	2808.7×	0.002	CLASP1
negative regulation of wound healing, spreading of epidermal cells	1	2407.4×	0.002	CLASP1
establishment of spindle orientation	1	2106.5×	0.002	CLASP1
obsolete vesicle targeting	1	1685.2×	0.002	CLASP1
microtubule organizing center organization	1	1404.3×	0.002	CLASP1
astral microtubule organization	1	1296.3×	0.002	CLASP1
microtubule anchoring	1	1296.3×	0.002	CLASP1
positive regulation of extracellular matrix disassembly	1	1203.7×	0.002	CLASP1
exit from mitosis	1	1053.2×	0.002	CLASP1
positive regulation of microtubule polymerization	1	674.1×	0.003	CLASP1
microtubule nucleation	1	624.1×	0.003	CLASP1
positive regulation of exocytosis	1	601.9×	0.003	CLASP1
regulation of focal adhesion assembly	1	601.9×	0.003	CLASP1
negative regulation of stress fiber assembly	1	581.1×	0.003	CLASP1
microtubule bundle formation	1	510.7×	0.003	CLASP1
basement membrane organization	1	510.7×	0.003	CLASP1
negative regulation of microtubule depolymerization	1	495.6×	0.003	CLASP1
positive regulation of epithelial cell migration	1	411.0×	0.003	CLASP1
establishment or maintenance of cell polarity	1	401.2×	0.003	CLASP1
mitotic spindle assembly	1	343.9×	0.003	CLASP1
mitotic spindle organization	1	271.8×	0.004	CLASP1
Golgi organization	1	133.8×	0.008	CLASP1
microtubule cytoskeleton organization	1	121.2×	0.009	CLASP1
cell division	1	46.2×	0.022	CLASP1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 3

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RNU4ATAC	0	0
CLASP1	0	0
CLASP1-AS1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
CLASP1	10	Binding:10

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	RNU4ATAC, CLASP1, CLASP1-AS1

Undrugged target profiles

3 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
RNU4ATAC	0	—
CLASP1	10	—
CLASP1-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06111950	Not specified	RECRUITING	Study of the Pathophysiology of RNU4ATAC and RTTN Associated Syndromes